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Vitamin D Analogs as Adjuvants in Chemotherapy

维生素 D 类似物作为化疗佐剂

基本信息

批准号：
7759554
负责人：
George P Studzinski
金额：
$ 20.59万
依托单位：
UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
1987
资助国家：
美国
起止时间：
1987-06-01 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7759554
关键词：
Adjuvant Anti-Inflammatory Agents Anti-inflammatory Antioxidants Antisense Oligonucleotides Attention Blood Blood specimen Calcitriol Cell Differentiation process Cell Line Cells Chemosensitization Clinical Trials Complement Data Development Differentiation Inducer Differentiation Therapy Environment Enzymes Event Exposure to Figs - dietary Food Preservatives Gene Expression Generations Genes Goals Growth Factor HL-60 Cells Human Imidazole Immunoblotting Immunoprecipitation In Vitro JUN gene Leukemic Cell Link MAP Kinase Gene MAPK14 gene MAPK8 gene MEKs Malignant Neoplasms Mammalian Cell Molecular Monitor Myeloid Leukemia Nature Nuclear Nuclear Localization Signal Orphan Disease Oxidation-Reduction Pathway interactions Patients Pharmaceutical Preparations Phase I Clinical Trials Phenotype Physiological Plants Plasmids Protein Kinase Proteins Public Health RAF1 gene Regulation Reverse Transcriptase Polymerase Chain Reaction Role Rosemary SB 203580 Sampling Schedule Series Shunt Device Signal Pathway Signal Transduction Source Subgroup Surface Surrogate Markers Techniques Testing Treatment Protocols Vitamin D Vitamin D Analog analog arm carnosol chemotherapy combat cost inhibitor/antagonist insight killings leukemia macrophage novel polyphenol programs public health relevance research study response rosmarinic acid salvin scaffold transcription factor translational study

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this proposal is to develop differentiation therapy to supplement the treatment regimens for human myeloid leukemia. We will focus on the identification of the most effective analogs (deltanoids) of the physiological form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D) administered at low concentrations to leukemia cells in culture and study alterations in gene expression and other cellular changes. The deltanoids and 1,25D induce monocytic/macrophage-like differentiation and will also be administered in combination with nontoxic substances currently used as food preservatives or additives, or with potential for such use, to maximize the differentiation activity of of the deltanoids. Further enhancement of the activity of these differentiation agents will be explored by the addition of an anti-inflammatory inhibitor of an intracellular signaling pathway. Established lines of leukemia, as well as samples of leukemic cells freshly obtained from patients, will be used for studies of of cell differentiation. The rationale is provided by previous observation that antioxidants provide a reducing environment and induce expression of genes which complement the differentiation-inducing actions of deltanoid-responsive genes. Insight into differentiation control will be obtained by examination of signaling pathways with particular attention to MAPK pathways and to transcription factors. This will be accomplished by adding pharmacological agents, antisense oligonucleotides, siRNAs, transcription factor decoys, and transfected plasmid constructs to study the molecular consequences of these manipulations , which will be determined by immunoblotting, quantitative RT-PCR, immunoprecipitation, and other standard techniques. Differentiating cells will be monitored by determination of surface markers as well as the activity and the expression of various enzymes. The information obtained in basic studies will be utilized to guide development of a new generation of deltanoids and deltanoid combinations with co- inducers, while translational studies on leukemic cells ex vivo will serve to identify subgroups of myeloid leukemias most suitable for the initiation of clinical trials. PUBLIC HEALTH RELEVANCE: Differentiation therapy, which depends on the activation of existing cellular programs rather than on toxic drugs to combat malignant tumors, is already effective as the treatment of some cancers. We propose to develop it as therapy for blood malignancy known as myeloid leukemia, which although kills approximately 15,000 people in USA every year, is unlikely to receive attention from commercial support for finding its cure. Thus, myeloid leukemia can be considered an orphan disease, and merits support from public sources for the development of novel therapy.

描述（由申请人提供）：